The effect of venlafaxine compared with other antidepressants and placebo in the treatment of major depression: a meta-analysis

Bauer M, Tharmanathan P, Volz HP, Moeller HJ, Freemantle N

CRD summary

The authors concluded that venlafaxine was clinically effective in achieving therapeutic response and remission in patients with major depression. There were limitations in reporting of review methods, but overall the authors’ conclusions reflected the evidence presented and were likely to be reliable.

Authors' objectives

To evaluate the efficacy and tolerability of venlafaxine for the treatment of major depressive disorders compared with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).

Searching

MEDLINE, EMBASE, The Cochrane Library and the authors’ own database of trials were searched up to April 2007. Search terms were not reported. Company archives of Wyeth (the manufacturer of venlafaxine) were searched for available unpublished data.

Study selection

Studies that compared venlafaxine with other antidepressant drugs for the treatment of major depressive disorders and studies that compared venlafaxine with placebo for the prevention of relapse in patients previously treated for major depressive disorders were eligible for inclusion. The review assessed response (generally defined as a 50% reduction in Hamilton Rating Scale Score, HAM-D), remission (defined as reaching a HAM-D score of 7 or less), drop-out for any cause, drop-out due to side effects and drop-out due to inefficacy.

The included studies compared venlafaxine with the following drugs: SSRIs (mostly fluoxetine and paroxetine, but also sertraline, citalopram and escitalopram); TCAs (imipramine, clomipramine, amitriptyline, dothiepin, amineptine and maprotiline); other antidepressants (bupropion, mirtazapine, moclobemide, reboxetine and trazodone); and placebo. Studies used varying doses of venlafaxine. Where reported, participants were adults and the duration of follow-up ranged from 14 days to three years. Most studies used the HAM-D or the Montgomery-Asberg Depression Rating Scale (MADRS) to measure outcomes.

The authors stated neither how studies were selected for inclusion nor how many reviewers performed the selection.

Assessment of study quality

One reviewer extracted data on the duration of follow-up, losses to follow-up, allocation concealment and blinding. Extracted data were checked by a second reviewer.

Data extraction

For each study, the numbers of events of interest were extracted and presented in tables. The authors did not state how many reviewers extracted results data.

Methods of synthesis

Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using two methods: a theoretically exact conditional likelihood method for fixed-effect analysis; and an empirically Bayesian numerical stimulation random-effects method. The number needed to treat was calculated using the DerSimonian and Laird Risk Difference method. Heterogeneity was assessed using the Breslow Day, Cochrane and I2 tests. Publication bias was assessed using the Begg-Mazumdar, Egger and Horbold-Egger methods.

Results of the review

Thirty-four RCTs compared venlafaxine with SSRIs (n=7,155). Eighteen RCTs compared venlafaxine with tricyclic antidepressants (n=2,769). Seven RCTs compared venlafaxine with other antidepressants (n=1,338), but only four (n not reported) provided data. Five RCTs compared venlafaxine with other antidepressants in treatment resistant depression (n=4,754). Three RCTs compared venlafaxine with placebo in the prevention of relapse or recurrence after major depressive episode (n=973). Most studies were double blinded. None reported allocation concealment.

Compared to SSRIs, venlafaxine was associated with a significant increase in response (OR1.15, 95% CI 1.02 to 1.29; 29 studies) and remission (OR 1.19, 95% CI 1.06 to 1.34; 23 studies). There was no significant difference between venlafaxine and SSRIs in overall drop-outs. There was no significant heterogeneity for response and some evidence of heterogeneity for remission (p=0.03, I2=38%).

Compared to TCAs, venlafaxine was associated with a significant increase in response using the exact method (OR 1.21, 95% CI 1.03 to 1.43; 16 studies), but there was no significant difference in response using a full random-effects model and no significant difference in remission rates. TCAs were associated with higher overall drop-out rates compared to venlafaxine (OR 0.77, 95% CI 0.65 to 0.90; 15 studies). There was some evidence of heterogeneity for response (p=0.06, I2=37%), but no evidence of heterogeneity for remission.

Compared to alternative antidepressants in patients with treatment resistant depression, venlafaxine was associated with a significant increase in response (OR 1.35, 95% CI 1.19 to 1.54; four studies) and remission (OR 1.35, 95% CI 1.20 to 1.52; five studies).There was no significant heterogeneity for either analysis.

Compared to placebo, venlafaxine was associated with a significant increase in relapse prevention (OR 0.37, 95% CI 0.27 to 0.51; three studies).

Authors' conclusions

Venlafaxine was clinically effective in achieving therapeutic response and remission in patients with major depression. Venlafaxine appeared more effective than SSRIs, at least as effective as tricyclics and more effective in treatment-resistant depression than comparators. Long-term venlafaxine was effective in reducing relapse after a major depressive episode.

CRD commentary

The review question was clearly stated. Inclusion criteria were appropriately defined for study design, participants and intervention. Relevant outcomes were clearly stated. Several relevant sources were searched. Unpublished data were provided by the manufacturer of venlafaxine, but no attempts were made to identify other unpublished studies; the potential for publication bias was assessed. It was unclear whether any attempts were made to minimise language bias. Methods were used to minimise reviewer error and bias in the assessment of validity, but it was not reported if similar methods were used for study selection or extraction of results data. Validity was assessed and results were reported. Studies were appropriately pooled using meta-analysis. Heterogeneity was assessed.

There were limitations in reporting of review methods, but overall the authors’ conclusions reflected the evidence presented and are likely to be reliable.

Implications of the review for practice and research

The authors did not state any implication for practice or research.

Funding

Wyeth Pharma GmbH. Several of the authors had received funding for research and/or consulting from various pharmaceutical companies.

Bibliographic details

Bauer M, Tharmanathan P, Volz HP, Moeller HJ, Freemantle N. The effect of venlafaxine compared with other antidepressants and placebo in the treatment of major depression: a meta-analysis. European Archives of Psychiatry and Clinical Neuroscience 2009; 259(3): 172-185

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.